Complement activation-related cardiac anaphylaxis in pigs: Role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function

J. Szebeni, Lajos Baranyi, Sándor Sávay, Michael Bodó, János Milosevits, Carl R. Alving, Rolf Bünger

Research output: Article

71 Citations (Scopus)

Abstract

Cardiac anaphylaxis is a severe, life-threatening manifestation of acute hypersensitivity reactions to allergens and drugs. Earlier studies highlighted an amplifying effect of locally applied C5a on the process; however, the role of systemic complement (C) activation with C5a liberation in blood has not been explored to date. In the present study, we used the porcine liposome-induced cardiopulmonary distress model for 1) characterizing and quantifying peripheral C activation-related cardiac dysfunction; 2) exploring the role of C5a in cardiac abnormalities and therapeutic potential of C blockage by soluble C receptor type 1 (sCR1) and an anti-C5a antibody (GS1); and 3) elucidating the role of adenosine and adenosine receptors in paradoxical bradycardia, one of the symptoms observed in this model. Pigs were injected intravenously with different liposomes [Doxil and multilamellar vesicles (MLV)], zymosan, recombinant human (rhu) C5a, and adenosine, and the ensuing hemodynamic and cardiac changes (hypotension, tachy- or bradycardia, arrhythmias, ST-T changes, ventricular fibrillation, and arrest) were quantified by ranking on an arbitrary scale [cardiac abnormality score (CAS)]. There was significant correlation between CAS and C5a production by liposomes in vitro, and the liposome-induced cardiac abnormalities were partially or fully reproduced with zymosan, rhuC5a, adenosine, and the selective adenosine A1 receptor agonist cyclopentyl-adenosine. The use of C nonactivator liposomes or pretreatment of pigs with sCR1 or GS1 attenuated the abnormalities. The selective A1 blocker cyclopentyl-xanthine inhibited bradycardia without influencing hypotension, whereas the A2 blocker 4-(2-{7-amino-2-(2-furyl)[1,2,4] triazolo[2,3-a][1,3,5]triazin-5-ylamino}ethyl)phenol (ZM-24135) had no such effect. These data suggest that 1) systemic C activation can underlie cardiac anaphylaxis, 2) C5a plays a causal role in the reaction, 3) adenosine action via A1 receptors may explain paradoxical bradycardia, and 4) inhibition of C5a formation or action or of A1-receptor function may alleviate the acute cardiotoxicity of liposomal drugs and other intravenous agents that activate C.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume290
Issue number3
DOIs
Publication statusPublished - márc. 2006

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Anaphylatoxins
Complement Activation
Anaphylaxis
Liposomes
Adenosine
Bradycardia
Electrocardiography
Swine
Zymosan
Hypotension
Adenosine A1 Receptor Agonists
Purinergic P1 Receptors
Xanthine
Ventricular Fibrillation
Phenol
varespladib methyl
Tachycardia
Pharmaceutical Preparations
Allergens
Cardiac Arrhythmias

ASJC Scopus subject areas

  • Physiology

Cite this

Complement activation-related cardiac anaphylaxis in pigs : Role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function. / Szebeni, J.; Baranyi, Lajos; Sávay, Sándor; Bodó, Michael; Milosevits, János; Alving, Carl R.; Bünger, Rolf.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 290, No. 3, 03.2006.

Research output: Article

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